Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy

Dziadziuszko, Rafał; Holm, Bente; Skov, B. G.; Østerlind, Kell; Sellers, MV; Franklin, W.; Bunn, P. A.; Varella‐Garcia, Marileila; Hirsch, F. R.

doi:10.1093/annonc/mdl407

Cited by 43 publications

(26 citation statements)

References 24 publications

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“…Previous studies using Western-blot, immunohistochemistry and real time PCR showed that EGFR is overexpressed in 27-83% of non-small-cell-lung cancer tissues [20][21][22]. In accordance with previous studies, we detected EGFR overexpression by Western-blot in primary nonsmall-cell-lung cancer patients with a frequency of 40% in our patient population.…”

Section: Discussionsupporting

confidence: 91%

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR

et al. 2009

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Signaling pathways activated by epidermal growth factor receptors (EGFRs) are important in lung carcinogenesis. New treatment strategies with EGFR-targeting drugs provided improvements in management of lung cancer. However, molecular mechanisms underlying resistance to these drugs need to be evaluated. Surgically resected samples were obtained from 50 patients with non-small-cell-lung cancer. PTEN, Mcl-1 and EGFR protein expression levels were evaluated by Western-blot. Direct sequencing was performed to investigate EGFR tyrosine kinase domain mutations. We detected c.2235-2249 (pGlu746-Ala750del) mutation in exon 19 in two patients with adenocarcinoma histology. Elevated expression levels of both Mcl-1 isoforms (Mcl-1S and Mcl-1XL) and EGFR proteins were found in 15 (30%) and 23 (46%) of the cases, respectively. Reduced PTEN protein expression levels were observed in 17 (34%) of the cases. PTEN expression level was reduced in 26% of cases that showed increased EGFR expression. Also, increased expression of Mcl-1 protein was observed in 26% of cases with EGFR overexpression. One of the cases harboring pGlu746-Ala750del mutation had increased levels of Mcl-1 and decreased PTEN expression levels. Our results indicate that, in addition to lack of PTEN expression, elevated levels of the Mcl-1 protein might be one of the important intrinsic mechanisms protecting non-small-cell-lung cancer cells from apoptosis induced by several compounds. Therefore, EGFR mutations in conjunction with evaluation of Mcl-1 and PTEN expression levels in large cohorts might provide important clues for improvements of new treatment strategies in non-small-cell-lung cancer management.

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Section: Discussionsupporting

confidence: 91%

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR

et al. 2009

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“…Both studies failed to demonstrate its clinical applicability (Bell et al, 2005;Dziadziuszko et al, 2006). EGFR qPCR was not predictive of response to treatment, disease control, progression-free survival or overall survival, nor did it correlate with FISH, immunohistochemistry or mRNA expression (Bell et al, 2005;Takano et al, 2005;Dziadziuszko et al, 2006Dziadziuszko et al, , 2007.…”

Section: Cishmentioning

confidence: 97%

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

2009

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“…In addition, a polymorphic variation in intron 1 of EGFR is predictive for response to EGFR TKI treatment in a study of pediatric solid tumors (10). Although relative protein levels do not seem to be predictors of EGFR TKI response, several studies suggest gene copy number as a predictor of response to EGFR TKIs (11)(12)(13)(14). Although amplification and mutation of EGFR frequently occur in cancers of other origins, breast cancers have a <10% rate of amplification and mutation of EGFR (15,16).…”

Section: Introductionmentioning

confidence: 99%

Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer Cells

et al. 2008

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Breast cancers are not responsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), although 30% of breast cancers overexpress EGFR. The mechanism of intrinsic resistance to EGFR TKIs in breast cancer is the focus of current studies. Here, we observed that EGFR remains tyrosine phosphorylated in breast cancer cells that proliferate in the presence of EGFR TKIs. In one such cell line, SUM229, inhibiting c-Src kinase activity with either a dominantnegative c-Src or a c-Src TKI decreased EGFR phosphorylation on Tyr 845 , Tyr 992 , and Tyr 1086 in the presence of EGFR TKIs. Conversely, overexpressing wild-type (wt) c-Src in the EGFR TKI-sensitive breast cancer cell line SUM149 increased EGFR kinase-independent EGFR tyrosine phosphorylation. In addition, in the presence of EGFR TKIs, inhibiting c-Src kinase activity decreased cell growth in SUM229 cells, and overexpressing wt-c-Src increased cell growth in SUM149 cells. We identified the receptor tyrosine kinase Met to be responsible for activating c-Src in SUM229 cells. Inhibiting Met kinase activity with a small molecule inhibitor decreased c-Src phosphorylation and kinase activation. In addition, inhibiting Met kinase activity in SUM229 cells decreased EGFR tyrosine phosphorylation and growth in the presence of EGFR TKIs. Stimulating Met kinase activity in SUM149 cells with hepatocyte growth factor increased EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. These data suggest a Met/c-Src-mediated signaling pathway as a mediator of EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. [Cancer Res 2008;68(9):3314-22]

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Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy

Abstract: In chemotherapy-treated NSCLC patients, EGFR gene copy number was positively associated with protein level but none of the features were predictive for either treatment response or survival.

Cited by 43 publications

References 24 publications

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer Cells

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